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64 Cards in this Set
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Blood and Lymph- Anticoagulants by Maloney
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Blood and Lymph- Anticoagulants by Maloney
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Treatment of DVT/PE vs AFib?
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Both use Immediate anticoagulation (Parenteral agent) and Long term anticoagulation (Oral agent), but in DVT/PE, you also do fibrinolysis in conjunction with parenteral (not in Afib because You don’t always know you have a clot, so you’re not considering fibrinolytic agents. Bleeding risk is too high)
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Colour of clots (thrombi) and their contents...
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Red clots are RBCs.
White clots are platelets. Treat by working on the thrombin or the clot itself. |
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What is the main difference between the pharmacological treatment of STEMI and NSTEMI?
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the use of thrombolytics (fibrinolytics). Don't use thrombolytics for nonSTEMI because the bleeding risk is too high when you use a thrombolytic and outweighs the benefit.
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Name the heparin agents. How are they administered?
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Unfractionated Heparin (UFH)
Low molecular weight heparin (LMWH) Enoxaparin (Lovenox) Dalteparin (Fragmin) Ardeparin (Normiflo) Tinzaparin (Innohep) *"-parin" *parenterally because if oral, they is destroyed *LMWH created from unfractionated heparin via depolymerization reactions |
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MoA of unfractionated heparin
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Accelerates the reaction between:
-Antithrombin and thrombin -Antithrombin and Factor Xa Heparin forms a complex with Antithrombin (AT). Approximately one‑third of heparin molecules contain a unique pentasaccharide sequence with high‑affinity binding to AT. This accelerates the reaction between AT and factor IIa (thrombin) or factor Xa by at least 1000 fold. Need 18 saccharide units (5.4 kDa) to form a ternary complex between heparin, antithrombin and thrombin Smaller chain lengths are sufficient to catalyze the reaction between antithrombin and factor Xa |
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Blood and Lymph- Anticoagulants by Maloney
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Blood and Lymph- Anticoagulants by Maloney
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Treatment of DVT/PE vs AFib?
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Both use Immediate anticoagulation (Parenteral agent) and Long term anticoagulation (Oral agent), but in DVT/PE, you also do fibrinolysis in conjunction with parenteral (not in Afib because You don’t always know you have a clot, so you’re not considering fibrinolytic agents. Bleeding risk is too high)
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Colour of clots (thrombi) and their contents...
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Red clots are RBCs.
White clots are platelets. Treat by working on the thrombin or the clot itself. |
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What is the main difference between the pharmacological treatment of STEMI and NSTEMI?
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the use of thrombolytics (fibrinolytics). Don't use thrombolytics for nonSTEMI because the bleeding risk is too high when you use a thrombolytic and outweighs the benefit.
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Name the heparin agents. How are they administered?
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Unfractionated Heparin (UFH)
Low molecular weight heparin (LMWH) Enoxaparin (Lovenox) Dalteparin (Fragmin) Ardeparin (Normiflo) Tinzaparin (Innohep) *"-parin" *parenterally because if oral, they is destroyed *LMWH created from unfractionated heparin via depolymerization reactions |
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MoA of unfractionated heparin
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Accelerates the reaction between:
-Antithrombin and thrombin -Antithrombin and Factor Xa Heparin forms a complex with Antithrombin (AT). Approximately one‑third of heparin molecules contain a unique pentasaccharide sequence with high‑affinity binding to AT. This accelerates the reaction between AT and factor IIa (thrombin) or factor Xa by at least 1000 fold. Need 18 saccharide units (5.4 kDa) to form a ternary complex between heparin, antithrombin and thrombin. Smaller chain lengths are sufficient to catalyze the reaction between antithrombin and factor Xa. |
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MoA of LMWH?
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Accelerates the reaction between:
-Antithrombin and Factor Xa |
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Pharmacokinetics of UFH vs LMWH?
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UFH:
-IV (usually) or subcutaneous -*Unpredictable anticoagulant effect -Monitor the aPTT LMWH: -Subcutaneous (usually) or IV -*Predictable anticoagulant effect -No monitoring of the aPTT -Can be used at home -Expensive |
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Clinical use of heparin
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Prevent thrombosis
-Prophylaxis and treatment Subcutaneous unfractionated heparin or LMWH -Anticoagulant of choice during pregnancy -warfarin is teratogenic (crosses placenta) Monitor therapy -UFH - Activated partial thromboplastin time (aPTT) -LMWH - Anti-factor Xa activity (only in certain situations) |
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Does heparin break up clots? well... does it?
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no, sir. it does not break up clots. It just prevents clots from expanding.
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Examples of when heparin can be clinically used?
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Pulmonary embolism
Deep vein thrombosis Thromboembolism during pregnancy Postoperative venous thrombosis Arterial embolism (eg. from atrial fibrillation) ST-elevation myocardial infarction (STEMI) Unstable angina (UA) and Non ST-elevation myocardial infarction (NSTEMI) Percutaneous coronary interventions (PCI) |
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Adverse Reactions of Heparin?
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Bleeding
Heparin induced Thrombocytopenia (HIT) Type I – rapid, mild, transient (not a big deal) Type II – delayed, sustained, severe (5-10 days after heparin initiated. If you don't take the heparin away, HIT is not going to go away, big drop in platelet) |
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UFH and to a lesser extent, LMWH binds to plasma proteins including platelet factor 4 (PF4). Where does Platelet Factor 4 come from?
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Activated platelets.
Heparin binds to PF4 which then binds to an antibody (via Fc receptor on the platelet. This causes a very strong platelet activation. Type II HIT happens 5-10 days after given heparin because this is an immune response and takes a while to build up the antibodies to your PF4/plt complex |
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HIT Type II summary
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Platelet factor 4 is released from activated platelets and binds to heparin
Antibodies are produced to the heparin-PF4 complex These antibodies bind to the heparin-PF4 complex This immune complex (heparin-PF4-IgG) binds to platelet Fc receptors resulting in platelet activation |
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What will happen to the platelet count with HIT type 2?
What is the predominant clinical presentation with HIT type 2? |
plt count goes down because you used up a lot of plts that form little clots.
the presentation most common is thrombosis (not excessive bleeding) |
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Possible consequences of HIT
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Platelet count can decrease by 50%
-1-5% of patients with UFH -About 1% with LMWH Thromboembolic complications -20% of HIT patients -Mortality in this group - as high as 30% -Permanent morbidity (e.g. limb loss) - 20-30% |
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Treatment of Heparin induced Thrombocytopenia?
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Heparin must be stopped
Thrombosis can be treated with other agents -Direct thrombin inhibitors |
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Should you give enoxaparin (a LMWH) to a patient who has HIT?
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no. no form of heparin for someone with HIT. it can still contribute to the problem.
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Adverse effects of Heparin
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Osteoporosis in patients on heparin for 3-6 months (like pregnant people):
-UFH stimulates bone resorption and decreases bone formation -LMWH appears to only decrease bone formation |
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Contraindications of Heparin
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-Active Bleeding
-Thrombocytopenia -Coagulation disorders -Increased risk of hemorrhage -Avoid after surgery of brain, spinal cord, or eye |
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Antidotes for Heparin
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Protamine sulfate:
-Forms a stable complex with heparin -With life threatening bleeding Precautions with protamine: -Can have anticoagulant effects -Anaphylactic reactions - diabetics who take protamine containing insulin |
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Fondaparinux (Arixtra). What is it a selective inhibitor for?
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Synthetic pentasaccharide that is a selective factor Xa inhibitor.
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Homework:
-Compare the MOA of fondaparinux with heparin -Will fondaparinux need monitoring by the aPTT? -Will fondaparinux cause as much HIT as UFH or LMWH? |
ok.
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Hirudo medicinalis: Medicinal Leech
-what is the name of the anticoagulant from the salivary glands? |
hirudin.
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What are the 2 thrombin inhibitors that we need to know?
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Lepirudin (Refludan)
-Recombinant derivative of hirudin Bivalirudin (Angiomax) -Bivalent analog of hirudin *both have '-rudin' in the name. **they are IV drugs (know that) |
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MoA of thrombin inhibitors
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-Directly bind to and inhibit thrombin
(heparin needs to bind to antithrombin III) -Effects are independent of anti-thrombin -Inhibits soluble (i.e. free) and fibrin-bound (i.e. in a clot) thrombin (heparin only inhibits soluble thrombin...still may have some clot expansion) |
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Clinical Use of thrombin inhibitors
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Heparin-induced thrombocytopenia:
-Lepirudin -Argatroban Heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI) -Bivalirudin Percutaneous coronary intervention (PCI) -Bivalirudin |
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Adverse Effects of Thrombin Inhibitors
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Bleeding
Allergic reactions -Lepirudin |
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MoA of Warfarin?
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Vitamin K antagonist (Koumadin)
Inhibits the synthesis of Vitamin K dependent clotting factors in the liver -Factors II, VII, IX and X Inhibits the synthesis of protein C and protein S -Endogenous anticoagulants |
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warfarin blocks the ____, which normally does what?
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Vitamin K epoxide reductase which normally recycles vitamin K (reduces it), so you don't have any carboxylated prothrombin (factors 2,7,9,10, protein C and S). So vitamin K stays in the oxidized form, so the clotting factors cannot be activated.
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Warfarin – Mechanism of Action Summary
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Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase.
Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders Factors II, VII, IX, and X, and Protein C and Protein S activatable. Vit KO is then reduced to Vit KH2 by vitamin KO reductase. Warfarin inhibits vitamin KO reductase, thereby blocking the formation of vitamin vitamin KH2. This prevents the carboxylation (and hence production) of vitamin K dependent coagulation factors. |
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Pharmacokinetics of Warfarin
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Oral or IV
Half life - 36 to 42 hours Peak effect: 72-96 hours Duration of Action: 2-5 days 97% bound to plasma proteins Mainly albumin Metabolized in liver Narrow therapeutic index Dosages vary greatly *takes long to get a peak effect because of the long half life of preexisting clotting factors |
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Clinical use and how do you monitor warfarin therapy?
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Prevent thrombosis:
-Takes 3-5 days to be effective -Start in conjunction with Heparin Monitor therapy: -Prothrombin time (PT) -Standardized PT time = International -Normalized Ratio (INR) |
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Clinical Use – Some Examples
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Thromboembolism
-Chronic atrial fibrillation -Prosthetic heart valve -People at risk following surgery, trauma or cancer Deep Venous Thrombosis or Pulmonary Embolism ST-elevation myocardial infarction (STEMI) *taken in conjunction with heparin (parenterally) because it works quicker than warfarin does |
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Warfarin Adverse Effects
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Bleeding
Skin necrosis--from widespread thrombosis -Occurs early in therapy (within the first 10 days) -Possibly due to reduced activity of Protein C Purple toe syndrome -Usually occurs within 3-10 weeks -Release of cholesterol microemboli from atheromatous plaques |
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What is Protein C?
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Endogenous anticoagulant.
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Teratogenicity of warfarin... compare the three trimesters.
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First trimester exposure:
A syndrome characterized by nasal hypoplasia and stippled epiphyseal calcifications that resemble chondrodysplasia punctata. 2nd and 3rd trimester exposure (less common): CNS abnormalities Fetal or neonatal hemorrhage |
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Pros and Cons of heparin in pregnancy with a mechanical heart valve
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Pro
-fetal risk lower -Not teratogenic Con -maternal risk higher -Valve thrombosis -Embolization -Osteoporosis -HIT type II |
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Contraindications of warfarin
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-same as heparin
-hepatic disease (vit. k factors made in the liver) -chronic alcoholism -pregnancy (teratogenic) Heparin-induced thrombocytopenia: -When used alone, it can cause venous limb gangrene or multicentric skin necrosis -The rapid loss of the endogenous anticoagulant, protein C, can cause a hypercoagulated state |
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Things to remember about warfarin... 97% of warfarin is bound to?
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-97% bound to plasma proteins
-Metabolized in liver -Narrow therapeutic index |
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What is/are the antidotes to warfarin?
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Vitamin K1 (phytonadione)
-Oral, IV or subcutaneous -Onset : 3-8 hours Fresh frozen plasma or prothrombin complex concentrate -Onset : immediate |
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Classifications of antiplatelet agents
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-Cyclooxygenase inhibitors
-ADP receptor antagonists -Glycoprotein Ilb/IIIa receptor antagonists -Phosphodiesterase inhibitors |
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Platelet adhesion, activation and aggregation, very brief summary
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-Damage to the vessel wall exposes collagen
-Von Willebrand’s factor secreted by the injured endothelium binds to collagen and the glycoprotein Ib (GP Ib) receptor on platelets causing adherence of platelets to the injured vessel wall -This starts the process of platelet activation -Platelets will release many factors including ADP and TxA2 (thromboxane) -ADP and TxA2 bind to their receptor on platelets to cause a conformational change in the GP IIb/IIIa receptor (aka fibrinogen receptor) located on the platelet membrane -This enables fibrinogen to bind to the GP IIb/IIIa receptor on 2 different platelets, causing platelet aggregation |
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Cyclooxygenase Inhibitors Agent(s) and mechanism of action
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Aspirin!
Irreversibly inhibits cyclooxygenase -Greater inhibition of COX-1 than COX-2 Blocks the production of TxA2 -Platelets |
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what is PGI2, and what does it do?
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Prostacyclin. Produced by prostaglandin H2 (via COX-2) in the endothelium. It's a vasodilator which inhibits platelet aggregation.
*Luckily, aspirin’s effect on endothelial cells is limited with low doses and short lived compared with its effect on TxA2 synthesis in platelets **Cyclooxygenase is inhibited for 6-8 hours |
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what is TxA2, and what does it do?
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Thromboxane A2. Produced by prostaglandin H2 (via COX-1) in the platelets. It's a vasoconstrictor that promotes platelet aggregation.
*This is where we want aspirin to work (against COX-1, TxA2) to prevent MI and platelet aggregation. **Cyclooxygenase is inhibited for the life of the platelet |
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Why is cyclooxygenase inhibited for only a short time in endothelial cells and forever in the platelet?
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Platelets don't have a nucleus so they cannot produce more cyclooxygenase enzyme.
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NSAIDs. Reversible or non? Help or hurt aspirin effects?
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Reversibly inhibit the formation of both PGI2 and TxA2
Chronic use of ibuprofen has been shown to counteract the beneficial effects of aspirin |
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COX-2 inhibitors and the heart...and vs aspirin in the GI.
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Not cardioprotective
Potentially ‘cardiotoxic’ Aspirin negates any GI benefit from using a COX-2 inhibitor |
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Clinical use of aspirin?
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STEMI, NSTEMI or Unstable angina
-Primary and secondary prevention -Acute treatment Percutaneous coronary intervention (PCI) (like angioplasty) -Acute -Chronic treatment afterwards Embolic stroke -Prevention -Acute treatment |
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What dose of aspirin to use for MI prevention?
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baby aspirin is good enough. any higher is no added benefit. 80mg is cool. Any more and you get more problems like bleeding.
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Adverse effects of aspirin.
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GI irritation and bleeding
-Inhibits the synthesis of prostaglandins that promote secretion of bicarbonate and mucous |
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ADP Receptor Antagonists Agents, how it works, how you take it.
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Clopidogrel (Plavix)
Prasugrel (Effient) "-grel" blocks the ADP receptor, hence you don't get the activation and the other stuff, so you get less platelet aggregation. Oral drugs, use similar to aspirin |
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GP IIb/IIIa Receptor Antagonists agents, how does it work, how do you take it?
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Abciximab (ReoPro)
Blocks GPIIb/IIIa receptor, so it inhibits the ability of fibrinogen to bind to the receptor and cross link the platelets, so you don't get platelet aggregation. IV (not for secondary prevention of MI), limited to PCI, UA or NSTEMI |
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Thrombolytic Agents
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Streptokinase (Streptase, Kabikinase)
-Isolated from beta-hemolytic streptococci Recombinant t-PA (tissue plasminogen activator): Alteplase (Activase) Reteplase (Retavase) Tenecteplase (TNKase) "-plase" |
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MoA of thrombolytics
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Catalyze the formation of plasmin from plasminogen
Plasmin degrades fibrin Helps promote dissolution of a clot *t-PA directly helps plasminogen turn into plasmin. Streptokinase needs to combine with a proactivator (another plasminogen) in order to turn plasminogen into plasmin |
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Clinical Use of thrombolytics
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Break up a clot
-STEMI -Deep vein thrombosis -Pulmonary embolism -Stroke Not for unstable angina or NSTEMI -Increased risk of death, MI and bleeding |
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Adverse effects of thrombolytics (and specifically streptokinase)
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Bleeding
Streptokinase -Allergic-anaphylactic reaction -Hypotension *streptokinase is 600$, the plases are 2700-3000$ *dark chocolate has some anti-platelet effects |